Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance

Morag Catherine Elliott McFadyen, H. L. McLeod, F. C. Jackson, William Thomas Melvin, J. Doehmer, Graeme Ian Murray

Research output: Contribution to journalArticle

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Abstract

The overexpression of human cytochrome P450 CYP1B1 has been observed in a wide variety of malignant tumours, but the protein is undetectable in normal tissues. A number of cytochrome P450 enzymes are known to metabolise a variety of anticancer drugs, and the consequence of cytochrome P450 metabolism is usually detoxification of the drug, although bioactivation occurs in some cases. in this study, a Chinese hamster ovary cell line expressing human cytochrome P450 CYP1B1 was used to evaluate the cytotoxic profile of several anticancer drugs (docetaxel, paclitaxel, cyclophosphamide, doxorubicin, 5-fluorouracil, cisplatin, and carboplatin) commonly used clinically in the treatment of cancer. The MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) as say was used to determine the levels of cytotoxicity. The key finding of this study was that on exposure to docetaxel, a significant decrease in sensitivity towards the cytotoxic effect's of docetaxel was observed in the cell line expressing CYP1B1 compared to the parental cell line (P = 0.03). Moreover, this difference in cytotoxicity was reversed by co-incubation of the cells with both docetaxel and the cytochrome P450 CYP1 inhibitor alpha-naphthoflavone. This study is the first to indicate that the presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug. (C) 2001 Elsevier Science Inc. All rights reserved.

Original languageEnglish
Pages (from-to)207-212
Number of pages5
JournalBiochemical Pharmacology
Volume62
Issue number2
DOIs
Publication statusPublished - 2001

Keywords

  • cytotoxicity
  • cytochrome P450
  • docetaxel
  • drug resistance
  • neoplasm
  • CHINESE-HAMSTER CELLS
  • HUMAN LIVER-MICROSOMES
  • BREAST-CANCER
  • OVARIAN-CANCER
  • IN-VITRO
  • METABOLISM
  • CYP1B1
  • 1B1
  • 6-ALPHA-HYDROXYTAXOL
  • BIOTRANSFORMATION

Cite this

Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. / McFadyen, Morag Catherine Elliott; McLeod, H. L.; Jackson, F. C.; Melvin, William Thomas; Doehmer, J.; Murray, Graeme Ian.

In: Biochemical Pharmacology, Vol. 62, No. 2, 2001, p. 207-212.

Research output: Contribution to journalArticle

McFadyen, Morag Catherine Elliott ; McLeod, H. L. ; Jackson, F. C. ; Melvin, William Thomas ; Doehmer, J. ; Murray, Graeme Ian. / Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. In: Biochemical Pharmacology. 2001 ; Vol. 62, No. 2. pp. 207-212.
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AB - The overexpression of human cytochrome P450 CYP1B1 has been observed in a wide variety of malignant tumours, but the protein is undetectable in normal tissues. A number of cytochrome P450 enzymes are known to metabolise a variety of anticancer drugs, and the consequence of cytochrome P450 metabolism is usually detoxification of the drug, although bioactivation occurs in some cases. in this study, a Chinese hamster ovary cell line expressing human cytochrome P450 CYP1B1 was used to evaluate the cytotoxic profile of several anticancer drugs (docetaxel, paclitaxel, cyclophosphamide, doxorubicin, 5-fluorouracil, cisplatin, and carboplatin) commonly used clinically in the treatment of cancer. The MTT (3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide) as say was used to determine the levels of cytotoxicity. The key finding of this study was that on exposure to docetaxel, a significant decrease in sensitivity towards the cytotoxic effect's of docetaxel was observed in the cell line expressing CYP1B1 compared to the parental cell line (P = 0.03). Moreover, this difference in cytotoxicity was reversed by co-incubation of the cells with both docetaxel and the cytochrome P450 CYP1 inhibitor alpha-naphthoflavone. This study is the first to indicate that the presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug. (C) 2001 Elsevier Science Inc. All rights reserved.

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